ReviewMetal complexes of thiosemicarbazones for imaging and therapy
Graphical abstract
Thiosemicarbazones are potent cytotoxins and with appropriate radiometals can be used for diagnostic medical imaging or therapy.
Highlights
► A review of the chemistry and biology of thiosemicarbazones. ► Their coordination chemistry with biologically relevant metals. ► Their applications in biomedicine for PET and SPECT imaging and therapy. ► Their mechanisms of actions in vitro and in vivo.
Introduction
It is a pleasure for me to be able to co-write this review as part of the volume of Inorganica Chimica Acta celebrating the many, varied and distinguished contributions made to Chemistry by Jon Zubieta. I first met Jon in the mid 1970s while he was on sabbatical at the Unit of Nitrogen Fixation in Brighton. We had several discussions on the molybdenum chemistry with hydrazine derived ligands in progress in my group and he left Brighton armed with some red crystals and the subsequent structure determination [1] was the start of a long and highly productive collaboration. This resulted in over 50 joint papers, mostly on rhenium and molybdenum chemistry. Later, we both independently became involved in technetium chemistry and I have followed with interest the significant advances he has made in this area. Jon was always immensely enthusiastic about science and our collaboration was a pleasure throughout. This review touches on two areas of mutual interest: the coordination chemistry of hydrazine derivatives and biomedical imaging.
Thiosemicarbazides first appeared in the literature in the late 1800s and thiosemicarbazones were reported as potential derivatisation agents for ketones and aldehydes in the 1900s. Their potential as ligands for a wide range of metals was realised and Jensen established the basis of their coordination chemistry in seminal papers in the 1930s [2], [3]. He proposed that coordination occurred via the sulfur and the azomethine nitrogen with formation of a five membered ring (Fig. 1A). In the presence of base loss of one of the ligand protons occurred, giving the ligand a uninegative charge. Without the advantage of X-ray structures he suggested that it was the exocyclic nitrogen that was deprotonated (Fig. 1B) whereas we now know that it is in fact a hydrazinic proton that is lost (see Fig. 1C).
These ligands can therefore provide a non-reducing source of anionic sulfur and also due to residual multiple bonding between C and S, the tendency for the sulfur to bridge metal ions is substantially less compared to thiolate. The ability of this class of ligands to act a source of ‘masked thiolate’ is one of the contributing factors to their ability to act as highly versatile donors towards a range of metal ions.
The bond distances for a typical square planar complex of a monothiosemicarbazone are shown in Fig. 2. They show fairly extensive delocalisation over the NC(NH2)S fragment but the N–N distance suggests little multiple bond character for this type of thiosemicarbazonate ligand.
Interesting as the coordination chemistry may be, the driving force for the study of these ligands has undoubtedly been their biological properties and the majority of the 3000 or so publications on thiosemicarbazones since 2000 have alluded to this feature. Some valuable reviews have appeared in this period on the chemistry and biochemistry of thiosemicarbazones [5], the structural features, biological activities and analytical applications of thiosemicarbazone complexes [6], the chemistry of copper complexes of thiosemicarbazones [7], [8] and structure activity relationships for the biological activity of nitrogen heterocycle derived monothiosemicarbazones [9]. This review covers more recent developments in the chemistry and biology of thiosemicarbazones in the author’s laboratory and elsewhere and focuses on two classes of thiosemicarbazone; those which act as tri- or tetradentate ligands. It is not intended to be comprehensive and rather uses selected examples to illustrate the main features of the chemistry and biochemistry of this versatile class of ligand.
Section snippets
Ligand types and coordination chemistry
Two principal classes of thiosemicarbazone with three potential donors (designated here as tridentate) have been investigated and are shown in Fig. 3. Those designated A have an anionic donor attached to the thiosemicarbazone whereas in class B the additional neutral donor atom is provided by an N-heterocyclic base. The type A ligands can lose two protons on coordination and complexes of the type [FeL2]− have been reported [10]. However, the biological properties of this type of ligand and its
Tetradentate thiosemicarbazones
The synthesis of bis(thiosemicarbazones) of diketones first appeared in 1902 [69] but it was not until the 1950s that their coordination chemistry was established by Baehr [70], [71], [72] who even at this early stage also commented on their potential as chemotherapeutic agents. As with the tridentate class discussed above this biological activity was to provide the driving force for much of the subsequent exploration of their chemistry.
Summary
Over the past decade the complexity of the biochemistry of interaction of thiosemicarbazones with cells has become apparent. The potent cytotoxicity of both the tridentate and tetradentate versions, either as free ligands or as metal complexes, is a result of simultaneous action on a diverse range of biological targets. Nevertheless some of the thiosemicarbazones are in clinical use or show promise and as more details of the biochemistry and SAR’s emerge their performance is capable of further
Acknowledgements
We are grateful to our colleagues in Oxford, Professor R. Muschel, Dr. V. Kersemans, Professor V. Gouverneur, Professor P. Blower at Kings College, London and Professor J. Lewis at MSKCC NY for valuable discussions about the mechanism of action of CuATSM.
Jonathan R. Dilworth obtained an MA degree from the University of Oxford in 1967 followed by a DPhil under the supervision of Professor J. Chatt at the University of Sussex in 1970. He worked as permanent member of staff at the Unit of Nitrogen Fixation from 1970 to 1985 when he took the Chair of Chemistry at the University of Essex. In 1997 he moved to the University of Oxford as Professor of Inorganic Chemistry where he remained until his retirement in 2009. Currently he is Emeritus Professor
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Jonathan R. Dilworth obtained an MA degree from the University of Oxford in 1967 followed by a DPhil under the supervision of Professor J. Chatt at the University of Sussex in 1970. He worked as permanent member of staff at the Unit of Nitrogen Fixation from 1970 to 1985 when he took the Chair of Chemistry at the University of Essex. In 1997 he moved to the University of Oxford as Professor of Inorganic Chemistry where he remained until his retirement in 2009. Currently he is Emeritus Professor at Oxford and holds an Honorary Professorship at the Department of Imaging Sciences, King’s College London. His recent research interests are in the applications of coordination chemistry in diagnostic molecular imaging, the development of new precursors for solid state materials with novel electronic properties and complexes with metal nitrogen multiple bonds. He has published over 300 papers on coordination chemistry involving complexes of titanium, molybdenum, tungsten, rhenium, technetium, ruthenium and copper.
Rebekka Hueting earned her MChem degree at Oriel College, Oxford in 2007 where she worked on a part II project with Professor Christopher J Schofield using dynamic combinatorial mass spectrometry for the inhibition of metalloenzymes. She remained at the University of Oxford to obtain a DPhil under the supervision of Professor Jonathan R. Dilworth and Professor Véronique Gouverneur in 2011. Her doctoral research focused on the development and mechanistic studies of radiolabelled copper bis(thiosemicarbazones) for cancer imaging. She currently holds a cross-disciplinary EPSRC postdoctoral research fellowship at the Department of Imaging Sciences and Bioengineering at King’s College, London. Her project investigates the radiolabelling of proteins using both 18F and metallic radionuclides for application in cardiovascular and cancer imaging.